Evidence for Altered GABA Signalling in Autism

The following post is based on research entitled: “GABA Receptor Binding Density in the Striatum of Individuals with Autism: Novel Findings for Consideration When Designing Human Clinical Autism Studies with Inhibitory Modulators.”

New findings from the Autism Neurocircuitry Lab at the Hussman Institute for Autism, led by Dr. Gene Blatt, Director of Neuroscience, with the research contributions of Krishna Subramanian, Ph.D.; a Postdoctoral Research Fellow, and Cheryl Brandenburg, Senior Laboratory Assistant.

Dr. Subramanian presented the following data from this study at the International Meeting for Autism Research, in May 2017.

A continuing study by researchers in the Autism Neurocircuitry Lab of the Hussman Institute for Autism has determined that individuals with autism display alterations in a brain circuit responsible for movement. Focusing on the effect of altered excitation and inhibition in specific regions of the brain on their connectivity and functioning, the researchers focused on levels of an inhibitory neurotransmitter called GABA (gamma-aminobutyric acid) in circuits within a region called the basal ganglia. Human movement is coordinated by circuits that run through the basal ganglia; connecting information from the cortex (which is responsible in part for cognition and social ability), and the cerebellum (which controls motor function amongst many other things). The basal ganglia are particularly involved in voluntary movement, and this region is of interest to autism researchers.

Circuits are formed in the brain by billions of neurons, or nerve cells. When these neurons communicate with each other a circuit is formed which allows the individual to perform a certain function. Neurons in the brain do not actually touch, but communicate messages (or impulses) to other neurons across synapses – minute gaps in between the neurons – by releasing molecules, or chemical messengers called neurotransmitters. These chemical signals travel across the synapse and are received by the next (postsynaptic) neuron. Two important neurotransmitters found in the human brain are:

• Gamma-aminobutyric acid (GABA); an inhibitory neuotransmitter which acts as a “hurdle” in the postsynaptic (receiving) neuron, reducing the initiation of new impulses or the continuation an existing chain of impulses.

• Glutamate; an excitatory neurotransmitter, which when received by a postsynaptic neuron helps to initiate and conduct impulses in the chain.

Under typical conditions these neurotransmitters interact in highly regulated ways to coordinate, synchronize, and fine-tune brain activity and information processing. Subramanian and his colleagues studied postmortem brain tissue from 21 individuals diagnosed with autism, and from 23 control individuals. The study focused on four regions of the basal ganglia:

• the caudate nucleus; these nuclei are associated with motor processes, but also play an important role in learning and in inhibitory control of action
• the putamen; this structure’s primary function is in regulation of movement
• the nucleus accumbens; this region plays an important role in in the cognitive processing of motivation and reward, as well as reinforcement learning. It also plays a role in the encoding of new motor processes
*Together, the above three regions form the striatum, which contains mostly GABAergic (inhibitory) neurons;
• the subthalamic nucleus; while the function of this component is not fully established, it is thought to play a role in action selection and switching, particularly the inhibition of motor plans that compete with desired movements. It contains primarily glutamatergic (excitatory) neurons

The researchers used a radioactive molecule to highlight receptors for GABA, a neurotransmitter that is of particular interest in autism research.
They found that the brains of individuals with autism exhibit higher levels of a type of GABA receptor called GABA-A in the striatum. While the striatum typically contains mostly inhibitory neurons, the subjects with autism displayed an increase in the A-type receptor.

Additionally, the brains of the subjects with autism showed a decrease in typical levels of the GABA-A receptor in the subthalamic nucleus. This is the only part of the basal ganglia which is primarily occupied by excitatory neurons, which transmit signals using glutamate.

Subramanian observed that this particular pattern of GABA-A in the different regions of the basal ganglia would together weaken the output of the basal ganglia to the cortex. The researchers hypothesize that providing augmented feedback in autism to overcome this weakened output could help with better motor, speech, and social learning and execution.

The discovery could have important implications for future clinical trials; drugs that selectively alter certain types of GABA signaling could potentially be used to ease repetitive behaviors, which have strong associations with the basal ganglia. Typically, clinical trials for autism target behaviors that have their origins in the cortex – such as social differences.

The next step for these Institute researchers will be to investigate the link between basal ganglia signaling and repetitive behaviors through comparison of the postmortem analyses that includes clinical data from the donors.